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Quercetin as a Systemic Chemopreventative Agent: Structural and Functional Mechanisms
E.E. Mendoza and R. Burd
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00001]
Polyphenols: Skin Photoprotection and Inhibition of Photocarcinogenesis
F. Afaq and S.K. Katiyar
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00002]
Natural Polyphenols and Cardioprotection
S. Lecour and K.T. Lamont
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00003]
Polyphenols and Neuroprotection against Ischemia and Neurodegeneration
B. Lin
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00004]
An Overview of Innovations in Analysis and Beneficial Health Effects of Wine Polyphenols
V. Rastija
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00005]
Analysis of Flavonoids in Foods and Biological Samples
A.M. González-Paramás, C. Santos-Buelga, M. Dueñas and S. González-Manzano
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00006]
Polyphenols and Cardiovascular Disease: A Critical Summary of the Evidence
F. Visioli and A. Davalos
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00007]
Editorial: Introduction to Polyphenols, Plant Chemicals for Human Health
Marcello Iriti
[BSP/MRMC/E-Pub/00008]
Paper Title: GPE and GPE analogues as promising neuroprotective agents
Ivana Cacciatore, Catia Cornacchia, Leonardo Baldassarre, Erika Fornasari, Adriano Mollica, Azzurra Stefanucci and Francesco Pinnen
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00009]
Vascular Effects of Phytoestrogens and Alternative Menopausal Hormone Therapy in Cardiovascular Disease
Vahide B. Gencel, Mina M. Benjamin, Shafik N. Bahou and Raouf A. Khalil
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00010]
CDC25 Phosphatase Inhibitors: An Update
Antonio Lavecchia, Carmen Di Giovanni and Ettore Novellino
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00011]
Cell adhesion molecules as pharmaceutical target in atherosclerosis
Shanhong Ling, Lina Nheu andPaul A. Komesaroff
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00012]
2,5-diketopiperazines as Neuroprotective Agents
Catia Cornacchia, Ivana Cacciatore, Leonardo Baldassarre, Adriano Mollica, Federica Feliciani and Francesco Pinnen
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00013]
Ascorbic acid: an old player with a broad impact on body physiology including oxidative stress suppression and immunomodulation. A review
Miroslav Pohanka, Jaroslav Pejchal, Svatava Snopkova, Katerina Havlickova, Jana Zdarova Karasova, Pavel Bostik and Jiri Pikula
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00014]
Tetracyclines: drugs with huge therapeutic potential
Farnaz Bahrami, David L Morris and Mohammad H. Pourgholami
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00015]
Lysophospholipids: potential Markers of Diseases and Infertility?
Beate Fuchs, Karin Müller, Uwe Paasch, and Jürgen Schiller
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00016]
Pleuromutilin and its derivatives-The lead compounds for novel antibiotics
You-Zhi Tang, Ya-Hong Liu and Jian-Xin Chen
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00017]
Editorial:
Arora Hot Topic: Looking Beyond The Obvious: Search For Novel Targets And Drugs For Reducing The Burden Of Infectious Diseases
[BSP/MRMC/E-Pub/00018]
Targeting Tuberculosis: A glimpse of promising drug targets
Neelima Arora and Amit Kumar Banerjee
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00019]
Daptomycin: A Review of Properties, Clinical Use, Drug Delivery and Resistance
Cláudia Vilhena and Ana Bettencourt
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00020]
Ru(Il)-Based Antimicrobials: Looking Beyond Organic Drugs
Ana I. Ramos, Teresa M. Braga and Susana S. Braga
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00021]
Targeting Strategies for Human Immunodeficiency Virus: A Combinatorial Approach
Shailendra K. Saxena, Ankur Gupta, Kamble Bhagyashree, Rakhi Saxena, Neelima Arora, Amit K. Banerjee,Anil K. Tripathi, Nimisha Gandhi and Madhavan P.N. Nair
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00022]
Carbohydrate mimics and lectins: a source of new drugs and therapeutic opportunities
José J. Reina and Anna Bernardi
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00023]
The Medicinal Chemistry Of (—)-Shikimic Acid
Amalia M. Estévez, Ramón J. Estévez and Juan C. Estévez
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00024]
Recent Progress on Fucosyltransferase Inhibitors
Pedro Merino, Tomás Tejero, Ignacio Delso, Ramon Hurtado-Guerrero, Asier Gómez‑SanJuan and David Sádaba
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00025]
Mycalamides, Pederin and Psymberin as Natural Carbohydrates and Potential Antitumor Agents: Past and Future Perspectives
Zbigniew J. Witczak, Ricky M. Rampulla Jr. and Ajay Bommareddy
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00026]
Carbohydrate based Potential Chemotherapeutic Agents: Recent Developments and their Scope in Future Drug Discovery
Vinod K. Tiwari, Ram C. Mishra, Anindra Sharma and Rama P. Tripathi
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00027]
Diels-Alder Cycloaddition in the Synthesis of 1-Azafagomine, Analogues, and Derivatives as Glycosidase Inhibitors
Daniela A. L. Salgueiro, Cristina E. A. Sousa, A. Gil Fortes and M. José Alves
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00028]
Advances in the Synthesis of Calystegines and Related Products and their Biochemical Properties
M.S. Pino-Gonzalez, N. Oña and A. Romero-Carrasco
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00029]
Spirocyclic Nucleosides In Medicinal Chemistry: An Overview
Raquel G. Soengas and Sandrina Silva
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00030]
Development of Aminoglycoside Antibiotics by Carbohydrate Chemistry
Lina Guo, Yue Wan, Xin Wang, Peng George Wang and Wei Zhao
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00031]
Fullerene Derivative as anti-HIV Protease Inhibitor: Molecular Modeling and QSAR Approaches
Medhat Ibrahim, Noha A. Saleh, Wael M. Elshemey and Anwar A. Elsayed
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00032]
Review of Theoretical Studies for Prediction neurodegenerative inhibitors
Francisco Prado-Prado and Isela García
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00033]
Evaluation of the Pharmacological Descriptors Related to the Induction of Antidepressant Activity and its Prediction by QSAR/QRAR Methods
Speranta Avram, Catalin Buiu, Daniel Duda-Seiman and Corina Duda-Seiman
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00034]
Pharmacological Descriptors Related to the Induction of Antidepressant Activity
Speranta AVRAM
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00035]
Relationship between phenol-induced cytotoxicity and experimental inhibition rate constant or a theoretical parameter
Seiichiro Fujisawa and Yoshinori Kadoma
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00036]
On the use of the metric rm2 as an effective tool for validation of QSAR models in computational drug design and predictive toxicology
Kunal Roy and Indrani Mitra
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00036]
Quantitative Structure-Activity Relationship (QSAR) Analysis to Predict Drug-Drug Interactions of ABC transporter ABCG2
Toshihisa Ishikawa, Hiroyuki Hirano, Hiakru Saito, Kazumi Sano and Yoji Ikegami
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00037]
Binding modes and pharmacophore modelling of thermolysin inhibitors
Mahmud Tareq Hassan Khan, Yimingjiang Wuxiuer and Ingebrigt Sylte
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00038]
QSAR in Oral Bioavailability: Specificity or Integrality?
Miguel Ángel Cabrera-Pérez, Hai Pham-The, Marival Bermejo, Isabel González Álvarez, Marta González Álvarez and Teresa M Garrigues
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00039]
Estimation of the Binding Free Energy by Linear Interaction Energy Models
Orazio Nicolotti, Marino Covertino, Francesco Leonetti, Marco Catto, Saverio Cellamare and Angelo Carotti
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00040]
A Critical View on Antimalarial Endoperoxide QSAR Studies
Róbson Ricardo Teixeira, José Walkimar de Mesquita Carneiro, Martha T. de Araújo and Alex G. Taranto
[Abstract] [FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00041]
Abstracts
Quercetin as a Systemic Chemopreventative Agent: Structural and Functional Mechanisms
E.E. Mendoza and R. Burd
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00001]
There is a growing focus on diet and the use of naturally abundant compounds as supplements because their properties have many potential health benefits with minimal side effects. The flavonol-type flavonoid quercetin has increased in popularity because it is a highly studied, multidimensional bioactive compound that possesses both antioxidant properties and the ability to modulate signal transduction pathways. Direct antioxidant properties may play a role in the abrogation of both DNA damage, but potentially of more importance quercetin, can also target multiple signaling pathways associated with oncogenesis and tumor progression, which include DNA damage, inflammation and obesity. Quercetin can also upregulate proteins that abrogate free radical damage, such as p53. The concurrent targeting of quercetin’s multiple bioactivities presents a potent chemopreventative strategy, but because bioavailability of quercetin is poor it will be necessary to develop quercetin analogs to maximize the full chemopreventative potential of the compound. This review will explore the structural and mechanistic properties of quercetin as they relate to its ability to act as a chemopreventative compound. A better understanding of quercetin’s mechanistic properties could aid in the rational design of more potent or bioavailable flavonol-type compounds.
[Back to top]
Polyphenols: Skin Photoprotection and Inhibition of Photocarcinogenesis
F. Afaq and S.K. Katiyar
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00002]
Polyphenols are a large family of naturally occurring plant products and are widely distributed in plant foods, such as, fruits, vegetables, nuts, flowers, bark and seeds, etc. These polyphenols contribute to the beneficial health effects of dietary products. Clinical and epidemiological studies suggest that exposure of the skin to environmental factors/pollutants, such as solar ultraviolet (UV) radiation induce harmful effects and leads to various skin diseases including the risk of melanoma and non-melanoma skin cancers. The incidence of non-melanoma skin cancer, comprising of squamous cell carcinoma and basal cell carcinoma, is a significant public health concern world-wide. Exposure of the skin to solar UV radiation results in inflammation, oxidative stress, DNA damage, dysregulation of cellular signaling pathways and immunosuppression thereby resulting in skin cancer. The regular intake of natural plant products, especially polyphenols, which are widely present in fruits, vegetables, dry legumes and beverages have gained considerable attention as protective agents against the adverse effects of UV radiation. In this article, we first discussed the impact of polyphenols on human health based on their structure-activity relationship and bioavailability. We then discussed in detail the photoprotective effects of some selected polyphenols on UV-induced skin inflammation, proliferation, immunosuppression, DNA damage and dysregulation of important cellular signaling pathways and their implications in skin cancer management. The selected polyphenols include: green tea polyphenols, pomegranate fruit extract, grape seed proanthocyanidins, resveratrol, silymarin, genistein and delphinidin. The new information on the mechanisms of action of these polyphenols supports their potential use in skin photoprotection and prevention of photocarcinogenesis in humans.
[Back to top]
Natural Polyphenols and Cardioprotection
S. Lecour and K.T. Lamont
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00003]
With more than 8000 polyphenols found in food (mainly, wine, tea, coffee, cocoa, vegetables and cereals), many epidemiological studies suggest that the intake of polyphenol-rich foods has a beneficial effect on a large number of cardiovascular risk factors, such as high blood pressure, high blood cholesterol, obesity, diabetes and smoking. The mechanisms involved in the cardioprotective effects of polyphenols are numerous and include antioxidant, vasodilator, anti-inflammatory, anti-fibrotic, antiapoptotic and metabolic. Most importantly, recent experimental data demonstrate that polyphenols can exert its cardioprotective effect via the activation of several powerful prosurvival cellular pathways that involve metabolic intermediates, microRNAs, sirtuins and mediators of the recently described reperfusion injury salvage kinases (RISK) and survivor activating factor enhancement (SAFE) pathways.
[Back to top]
Polyphenols and Neuroprotection against Ischemia and Neurodegeneration
B. Lin
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00004]
Neuroprotection of polyphenols in medical plants is getting attention in the world. Scutellaria baicalensis, paeonia veitchii and paeonia suffruticosa have been extensively studied in the last 10 years and show multi-function. They are neuroprotectants, antioxidants, anti-inflammatory and antithrombic agents as well as vasoconstriction inhibitorsand amyloid-peptide (Aβ) cleaners by means of their polyphenols: baicalin, baicalein, wogonin (in scutellaria), and
paeonol, paeonoside, paeoniflorin (PF) and 1, 2, 3, 4, 6-Penta-O-galloyl-beta-D-glucose (PGG) (in paeonia veitchii and paeonia suffruticosa). Other 4 medical plants: astragali, ligusticum wallichii, angelica sinensis and carthamus tinctorius (saffron) have been the major medicines to treat ischemia for hundreds of years in China, Korea and Japan. Our recent experimental studies demonstrated the neuroprotective efficacy of the combination of these phyotmedicines on mitigating brain infarction and global ischemia as well as preventing the neurodegeneration following ischemia. Owing to their multi-function, including improving cerebral blood circulation, they therefore have the potential to alleviate the symptoms of degenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD). Pharmacology of the 7 herbs and their major relative polyphenols is depicted in the article.
[Back to top]
An Overview of Innovations in Analysis and Beneficial Health Effects of Wine Polyphenols
V. Rastija
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00005]
Polyphenols are natural compounds that show a wide spectrum of biological actions potentially beneficial for the human health. Wine is an alcoholic beverage that contains a large amount of polyphenols extracted from grapes during the processes of vinification. These molecules are associated with anticancerogenic, antidiabetic, neuroprotective, hormonal, antimicrobial, cardioprotective, and other health effects of wine. The present review provided an overview of well know and recent achievement in analytical methodology for the analysis of polyphenols in wine, and their biological activities.
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Analysis of Flavonoids in Foods and Biological Samples
A.M. González-Paramás, C. Santos-Buelga, M. Dueñas and S. González-Manzano
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00006]
Flavonoids are a major class of plant phenolics that are widely distributed in the human diet and have been related to health promotion. They may occur in their natural sources in free forms (aglycones), as glycosylated or acylated derivatives, or as oligomeric and polymerized structures. This structural diversity affects their physicochemical behavior and complicates their analysis. Thus, there is not a single standardized procedure that can be recommended for all flavonoid groups and/or type of samples, and the procedures have to beoptimized depending on the nature of the sample and the target analytes. Furthermore, when dealing with the analysis of flavonoids biological samples (i.e., human and animal fluids and tissues) some differential aspects have to be taken into account; the nature of the compounds that can be found in those samples may differ from that present in plants and food, and flavonoids and metabolites occur in much lower concentrations, which make their analysis still more challenging. In this review the main techniques for extraction and analysis of flavonoids in foodstuffs and biological fluids are revised, as well as their occurrence in foods and beverages and available databases.
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Polyphenols and Cardiovascular Disease: A Critical Summary of the Evidence
F. Visioli and A. Davalos
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00007]
Epidemiological studies are clear: diets in which plant foods provide the major portion of caloric intake, e.g. the Mediterranean and the Japanese diets, are associated with a reduced risk of certain degenerative diseases like cancer and atherosclerosis. Although fats and proteins in plants, as opposed to those of animal origin, are responsible to some extent for these protective effects, the contribution of other plant food components may also be relevant. In the past few years, research on polyphenols has remarkably expanded and is unveiling several biological activities of these compounds. Alas, the marketing departments of several industries are jumping ahead of solid scientific evidence; as a consequence, unsubstantiated claims are being made and whole foods or fortified, enriched, or enhanced foods are being created and sold. Science is beginning to corroborate some of these claims, but much more research is needed and several myths are to be disproven. In this mini-review we critically discuss the current limitations of polyphenol research and we contend that, in addition to their putative antioxidant action, several biochemical and physiological processes might be influenced by polyphenols.
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Editorial: Introduction to Polyphenols, Plant Chemicals for Human Health
Marcello Iriti
[BSP/MRMC/E-Pub/00008]
Polyphenols are a large group of phenylalanine derivatives, structurally characterized by the presence of least two aromatic phenolic rings (C6-OH) (they are, literally, compounds with multiple phenols). They are exclusively produced by plant organisms. In particular, an aromatic ring - formed by the condensation of 3 malonyl Co-A units - is linked to the phenylpropanoid moiety arising from phenylalanine. These phytochemicals include thousands of metabolites and are being grouped into three main classes: flavonoids (C6-C3--C6), stilbenes (C6-C2–C6) and proanthocyanidins (or condensed tannins) [(C6–C3–C6)n] [1].
The ecological role of polyphenols - For the producing organisms, i.e. plants, polyphenols are secondary metabolites with a plethora of ecological functions. In general, they do not play any role in the plant’s primary metabolic requirements, i.e. the synthesis of biomacromolecules (carbohydrates, lipids, proteins, and nucleic acids). Rather, phytochemicals allow interactions of plants with the environment, increasing their overall ability to survive and overcome local challenges [2]. Polyphenols exert protective functions as antioxidant and UV-absorbing agents. They defend plant against pathogens (fungi, bacteria, virus) and environmental pollutants, and are involved in plant-plant interaction/competition (allelopathy) [3]. These compounds also play a role in herbivore deterrence - mainly against phytophagous insect - acting as agonists or antagonists of neurotransmitter systems or forming structural analogues of (animal) endogenous hormones [4-6]. Finally, the plant’s fitness greatly benefits from secondary metabolites which confer colours and scents to flowers and fruits, thus playing important roles in reproduction (attraction for pollinators and seed dispersal) [7].
Polyphenols in the human diet - As components of (food) plants, polyphenols entered the diet since the early steps of human evolution, though the advent of agriculture, approximately 10,000 years ago. This modified the human nutritional behaviour and, consequently, the (plant) food-human co-evolution [1]. Nowadays, in Western populations, the daily intake of polyphenols has been estimated to be ~ 1000 mg, though there is no relation between the quantity of polyphenols in foods and their bioavailability [8]. In any case, epidemiological studies have repeatedly shown an inverse association between the risk of chronic diseases and the consumption of polyphenol-rich diets. For instance, in a meta-analysis including more than 250,000 individuals, the relative risk of stroke was significantly lower in subjects consuming >5 servings/d of fruit and vegetables compared with those consuming <3 servings/d [9]. In the European Prospective Investigation into Cancer and Nutrition study, the intake of vegetables, legumes and fruit was significantly associated with reduce risk of cardiovascular disease mortality in a diabetic population (>10,000 individuals) [10]. However, confounding factors may generate an misinterpretation and association is not always the result of causality: many further studies are needed before we can prove that these associations do not arise from casualness.
Polyphenol structures - The flavonoid basic chemical structure is the flavan nucleus, consisting of 15 carbon atoms arranged in three rings (C6–C3–C6): two aromatic rings (A and B) connected by a three-carbon-atom heterocyclic ring, an oxygen-containing pyran ring (C) (Fig. 1). The main classes of flavonoids (flavanones, flavones, flavonols, flavanols, isoflavonoids, and anthocyanidins) differ in the level of oxidation and saturation of the C ring, while individual compounds within a class vary in the substitution pattern of the A and B rings [11].
Anthocyanidins are the most abundant pigments in the plant external tissues. Their conjugated derivatives, anthocyanins, mainly bound to sugars (glycones), hydroxycinnamates or organic acids, are water-soluble pigments conferring blue, dark blue, red and purple hues to flowers, fruits and other organs. Anthocyanins are structurally based on six aglycones/anthocyanidins – malvidin, cyanidin, delphinidin, peonidin, pelargonidin, and petunidin – which differentiate on the basis of number and position of their hydroxyl groups and their degree of methylation (Fig. 1) [12]. Flavonols mainly include kaempferol, quercetin, and myricetin aglycones, whereas apigenin and luteolin are widely-diffused flavones (Fig. 1). Flavan-3-ols (or flavanols) provide catechins, the monomeric units for proanthocyanidin biosynthesis [13] (Fig. 1). Flavanones are typical of citrus fruits (genus Citrus), such as the aglycones hesperetin and naringenin [14]. Isoflavonoids, also known as phytoestrogens, are important constituents of Fabaceae, including the soy genistein and daidzein [15]. Molecules belonging to the stilbene family (C6–C2–C6) are almost exclusively present in the genus Vitis, and possess the basic chemical structure based on the trans-resveratrol skeleton (Fig. 1). Stilbenes comprise piceids, pterostilbenes, and viniferins that are glucosides, dimethylated derivatives, and oligomers of resveratrol, respectively [16]. Proanthocyanidins [(C6–C3–C6)n] - also known as condensed tannins or simply tannins - are both oligomeric and polymeric compounds arising from flavanol unit condensation. Common monomers include catechin epimers [(+)-catechin and (-)-epicatechin], whose polymerization degree ranges mainly between 3 and 11 (Fig. 1) [17].
Antioxidant activity - One of the most investigated biological activities of polyphenols is their antioxidant power, though they also possess a plethora of more or less correlated properties, such as antimutagenic, anti-inflammatory, antitumoral, antihypertensive, cardio- and neuroprotective activities [18]. In particular, flavonoids act as antioxidants by donating electrons and stopping radical chains [19]. This activity is attributed to the phenolic hydroxyls, increasing with the number of OH groups in A and B rings. The structural requirements considered to be essential for effective radical scavenging by flavonoids are the presence of a 3’,4’-dihydroxy group (o-diphenolic group, a catechol structure) on the B ring, and a double bond between C2 and C3 (Δ2,3) conjugated with a keto function at C4 of the C ring. Hydroxyl groups on the B ring donate hydrogen and an electron to radical species, stabilizing them and giving rise to a relatively stable flavonoid radical. The C2–C3 double bond and the 4-keto group are responsible for electron delocalization from the B ring. Hydroxyl groups in positions 3 and 5, in combination with 4-oxo function and C2–C3 double bond, contribute to further enhance the radical scavenging activity [20-23].
In conclusion, it is noteworthy that natural products play major roles in the discovery of lead compounds for the development of drugs to treat human diseases: approximately one-half of all the drugs registered worldwide in the 25-year period prior to 2007 were natural products or their synthetic derivatives, though much of nature’s array of healthful molecules still remains to be explored [24].
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[19] Rice-Evans, C. Flavonoid antioxidants. Curr. Med. Chem., 2001, 8, 797-807.
[20] Heim, K.E.; Tagliaferro, A.R.; Bobilya, D.J. Flavonoid antioxidants: Chemistry, activity and structure-activity relationships. J. Nutr. Biochem., 2002, 13, 572-584.
[21] Amic, D.; Davidovic-Amic, D.; Besslo, D.; Trinajstic, N. Structure-radical scavenging activity relationships of flavonoids. Croat. Chim. Acta, 2003, 76, 55-61.
[22] Soobrattee, M.A.; Neergheen, C.S.; Luximon-Ramma, A.; Aruoma, O.I.; Bahorun, T. Phenolics as potential antioxidant therapeutic agents: Mechanism and actions. Mutation Research, 2005, 579, 200-213.
[23] Seyoum, A.; Asres, K.; El-Fiky, F.K. Structure-radical scavenging activity relationships of flavonoids. Phytochemistry, 2006, 67, 2058-2070.
[24] Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod., 2007, 70, 461-477.
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Paper Title: GPE and GPE analogues as promising neuroprotective agents
Ivana Cacciatore, Catia Cornacchia, Leonardo Baldassarre, Erika Fornasari, Adriano Mollica, Azzurra Stefanucci and Francesco Pinnen
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00009]
The tripeptide glycine-proline-glutamate (GPE) is the naturally cleaved N-terminal tripeptide of insulin-like growth factor-1 (IGF-1) in brain tissues by an acid protease. Although GPE does not bind to IGF-1 receptors and its mode of action is not clear, in vitro studies have demonstrated its ability to stimulate acetylcholine and dopamine release, as well as to protect neurones from diverse induced brain injures. More importantly, GPE has been shown to have potent neuroprotective effects in numerous animal models of hypoxic-ischemic brain injury and neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s diseases. As a consequence, GPE was suggested to be a potential target for the rational design of neuroprotective agents. Unfortunately, the use of GPE as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties.
This review will focus on structural modifications performed on the GPE molecule in order to obtain bioactive analogues with increased pharmacokinetic profile useful for the treatment of central nervous system (CNS) injures and neurodegenerative disorders.
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Vascular Effects of Phytoestrogens and Alternative Menopausal Hormone Therapy in Cardiovascular Disease
Vahide B. Gencel, Mina M. Benjamin, Shafik N. Bahou and Raouf A. Khalil
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00010]
Phytoestrogens are estrogenic compounds of plant origin classified into different groups including isoflavones, lignans, coumestans and stilbenes. Isoflavones such as genistein and daidzein are the most studied and most potent phytoestrogens, and are found mainly in soy based foods. The effects of phytoestrogens are partly mediated via estrogen receptors (ERs): ERa, ERβ and possibly GPER. The interaction of phytoestrogens with ERs is thought to induce both genomic and non-genomic effects in many tissues including the vasculature. Some phytoestrogens such as genistein have additional non-ER-mediated effects involving signaling pathways such as tyrosine kinase. Experimental studies have shown beneficial effects of phytoestrogens on endothelial cells, vascular smooth muscle, and extracellular matrix. Phytoestrogens may also affect other pathophysiologic vascular processes such as lipid profile, angiogenesis, inflammation, tissue damage by reactive oxygen species, and these effects could delay the progression of atherosclerosis. As recent clinical trials showed no vascular benefits or even increased risk of cardiovascular disease (CVD) and CV events with conventional menopausal hormone therapy (MHT), phytoestrogens are being considered as alternatives to pharmacologic MHT. Epidemiological studies in the Far East population suggest that dietary intake of phytoestrogens may contribute to the decreased incidence of postmenopausal CVD and thromboembolic events. Also, the WHO-CARDIAC study supported that consumption of high soybean diet is associated with lower mortalities from coronary artery disease. However, as with estrogen, there has been some discrepancy between the experimental studies demonstrating the vascular benefits of phytoestrogens and the data from clinical trials. This is likely because the phytoestrogens clinical trials have been limited in many aspects including the number of participants enrolled, the clinical end points investigated, and the lack of long-term follow-up. Further investigation of the cellular mechanisms underlying the vascular effects of phytoestrogens and careful evaluation of the epidemiological evidence and clinical trials of their potential vascular benefits would put forward the use of phytoestrogens as an alternative MHT for the relief of menopausal symptoms and amelioration of postmenopausal CVD.
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CDC25 Phosphatase Inhibitors: An Update
Antonio Lavecchia, Carmen Di Giovanni and Ettore Novellino
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00011]
The cell division cycle 25 (CDC25) family of proteins is a group of highly conserved dual-specificity phosphatases. They are key regulators of normal cell division and the cell response to DNA damage, and play a fundamental role in transitions between cell cycle phases during normal cell division, via the activation of CdK/cyclin complexes. Their abnormal expression, detected in a number of tumors, often correlated with a poor clinical prognosis, implies that their dysregulation is involved in malignant transformation. Thus, inhibition of these proteins represents an attractive therapeutic target in oncology, as evidenced from many patents and papers published on the subject in recent years. Hence, this review aims to provide an overview of recent developments in the field of CDC25 phosphatase inhibitor design since 2008.
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Cell adhesion molecules as pharmaceutical target in atherosclerosis
Shanhong Ling, Lina Nheu andPaul A. Komesaroff
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00012]
Cell adhesion molecules (CAMs) are transmembrane proteins that mediate adhesion and interactions between cells or cell and extra-cellular matrix. Increased expression and activation of CAMs in vascular endothelial cells and circulating leukocytes, as occurring in the settings of inflammation, hypercholesterolemia, hypertension and diabetes, stimulates leukocyte recruitment into the vascular endothelium, an important step in the pathogenesis of atherosclerosis. CAMs are a potential therapeutic target in clinical practice and in recent years pharmaceutical agents with specific effects on the production and function of these molecules have been studied and developed. This article reviews recent progress regarding pathophysiology of CAMs in atherogenesis and pharmaceutical products or chemicals that are active against CAMs, and assesses the possibilities for clinical developments in this area that might enhance the prevention, monitoring and treatment of atherosclerotic cardiovascular diseases.
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2,5-diketopiperazines as Neuroprotective Agents
Catia Cornacchia, Ivana Cacciatore, Leonardo Baldassarre, Adriano Mollica, Federica Feliciani and Francesco Pinnen
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00013]
2,5-diketopiperazines are the simplest cyclic peptides found in nature, commonly biosynthesized from amino acids by different organisms, and represent a promising class of biologically active natural products. Their peculiar heterocyclic structure confers high stability against the proteolysis and constitutes a structural requirement for the active intestinal absorption. Furthermore, the diketopiperazine-based motif is considered as a novel brain shuttle for the delivery of drugs with limited ability to cross the blood-brain barrier (BBB) and can be proposed as an ideal candidate for the rational development of new therapeutic agents. Although these cyclic peptides have been known since the beginning of the 20th century, only recently have they attracted substantial interest with respect to the wide spectrum of their biological properties, including antitumor, antiviral, antifungal, antibacterial and antihyperglycemic activities. In addition to these, the most challenging function of the diketopiperazine derivatives is related with their remarkable neuroprotective and nootropic activity. The aim of the present paper is to provide an overview of the two major classes of diketopiperazines, the TRH-related and the unsaturated derivatives both characterized by a significant ability to protect against neurotoxicity in several experimental models.
The neuroprotective profile of these compounds suggests that they may have a future utility in the therapy of neuronal degeneration in vivo, potentially through several different mechanisms.
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Ascorbic acid: an old player with a broad impact on body physiology including oxidative stress suppression and immunomodulation. A review
Miroslav Pohanka, Jaroslav Pejchal, Svatava Snopkova, Katerina Havlickova, Jana Zdarova Karasova, Pavel Bostik and Jiri Pikula
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00014]
Ascorbic acid is a low molecular weight antioxidant well known as anti-scorbut acting vitamin C in humans, primates and guinea pigs. This review summarizes basic data about ascorbic acid in its physiological action point of view. It is divided into biochemistry of ascorbic acid synthesis, mechanism of antioxidant action and participation in anabolism, pharmacokinetics and excretion, exogenous ascorbic acid immunomodulatory effect and participation in infectious diseases, impact on irradiation and intoxication pathogenesis, and supplementary demands. The primary intention was to consider ascorbic acid not only as an antioxidant but also as a chemical compound affecting multiple pathways with a potential beneficial impact in many diseases and processes in human body.
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Tetracyclines: drugs with huge therapeutic potential
Farnaz Bahrami, David L Morris and Mohammad H. Pourgholami
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00015]
Tetracyclines are an amazing class of chemical agents with multiple therapeutic potential. Structural modification of the original natural tetracyclines led to the synthesis and development of doxycycline and minocycline, compounds with higher lipophilicity, better oral pharmacokinetics and higher potency. Due to diverse pharmacological properties, these drugs are now under extensive investigation for use in the treatment of various disparate diseases. In recent years, several studies have conclusively reported anti-inflammatory, immune-modulating and neuroprotective effects of these compounds. There are currently over 200 ongoing clinical trials on tetracyclines. These studies extend over a wide range of diseases including dermatological diseases, behavior and mental disorders, immune system disorders, cardiovascular diseases, and cancer. In this review we will discuss the chemistry and pharmacology of these agents, and describe how their inhibitory effect on matrix metalloproteinase and on pro-inflammatory cytokines has kindled renewed interest in them. Based on the reports from pre-clinical and clinical trials, the therapeutic potential and application of tetracyclines may well be redefined and extensively extended.
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Lysophospholipids: potential Markers of Diseases and Infertility?
Beate Fuchs, Karin Müller, Uwe Paasch, and Jürgen Schiller
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00016]
The in vivo concentration of lysophospholipids (LPL) such as lysophosphatidylcholine (LPC) increases under different pathological conditions and, thus, LPL attract nowadays considerable diagnostic and pharmacological interest. LPL are particularly interesting because they possess pro- and anti-inflammatory properties and can be generated by two completely different pathways: either by the influence of (a) phospholipases and (b) different reactive oxygen species (ROS) that are generated in significant amounts under inflammatory conditions. This review provides a summary of the mechanisms by which LPL can be generated under in vitro and in vivo conditions. The focus will be on lysophosphatidylcholine (LPC) because this LPL is most abundant among all LPL and was, thus, most intensively studied so far. Additionally, biochemical, chromatographic and spectroscopic methods of LPL and LPC determinations will be discussed. Finally, the effects of LPL as signaling molecules and their roles in different pathologies such as infertility, cancer, atherosclerosis or inflammatory diseases are discussed. Special emphasis will be on the role of LPL in reproduction failures related to poor semen quality and, in that context, the potential role of LPC as a disease-indicative molecule.
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Pleuromutilin and its derivatives-The lead compounds for novel antibiotics
You-Zhi Tang, Ya-Hong Liu and Jian-Xin Chen
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00017]
Due to the rapid onset of resistance to most antibacterial drugs, research efforts are focusing on new classes of antibacterials with different mechanisms of action from clinically used antibacterials. Pleuromutilin derivatives have received more and more scientific attention for their unique mechanism of action. Two pleuromutilin derivatives, tiamulin and valnemulin have been successfully developed as antibiotics for veterinary use. Retapamulin, another pleuromutilin derivative has been approved for use in humans in April 2007 by Food and Drug Administration (FDA). It has been shown that there is rarely cross-resistance between pleuromutilin derivatives and other antimicrobial agents, and the development of resistance bacterial is still low. This review will demonstrate mechanism of action of pleuromutilin derivatives and reveal the structure-activity relationship (SAR) of pleuromutilin derivatives. Additionally, the pleuromutilin antibacterial derivative agents in the market, such as tiamulin, valnemulin and retapamulin, will be discussed. It is proposed that new antibacterial agents might be developed from pleuromutilin derivatives in the future.
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Editorial:
Arora Hot Topic: Looking Beyond The Obvious: Search For Novel Targets And Drugs For Reducing The Burden Of Infectious Diseases
[BSP/MRMC/E-Pub/00018]
Life is not easy, it never was. With every breath we are exposed to hundreds of infections, every passing second, a new fear of catching one infection or the other inflicts our mind. Infectious diseases claim more lives every year than all the casualties of war since historic times. Infectious agents who live in, on and around us have emerged as biggest scourge of mankind causing significant morbidity and mortality. Every year, millions lose lives while others learn to live in the dark shadow of fear, forced to wait for their turn. The “big three” HIV, Tuberculosis and Malaria kill more than five millions annually and undermine the health and well being of the people downtrodden with poverty lacking access to healthcare. Besides, often overlooked neglected infectious diseases (NID) have emerged and affect a significant proportion of population in resource-poor settings in developing countries.
Unfortunately, prospects of curbing infectious diseases seem so bleak even now despite all the technological advances. Despite the avalanche of information resulting from genome projects, the number of drugs, developed or the ones still in pipeline are few, clearly indicating a widening innovation gap. Genomic revolution has fallen short of its promises of turning table in our crusade against infectious diseases. Decline in development of anti-infective drugs can be partly attributed to drift in focus and policies and loss of economic motivation of Pharmaceutical industries which have curtailed their anti-infective research programs to pursue more rewarding and lucrative field of lifestyle diseases.
Our attempts to battle these infections are quite akin to snake and ladder game where the happiness of victory over one disease is soon tarnished by emergence of a new disease or a devastating pathogen. Diseases once confined to one geographical region are now gripping countries and regions where they were virtually unknown. These diseases are no longer marked by boundaries set by regions, sex, and economic status and affecting mankind globally.
Reemergence and resurgence of diseases once thought to be conquered has raised an alarm in the scientific community. Increasing resistance to drugs once perceived as “magic bullets” is another prime concern. The pathogens often called as “messengers of deaths” evolve at such rapid rate and manage to defy our tailor-made strategies and drugs that it becomes impossible to get ahead of them in the race. Reports of spread of multi-drug resistant strains of the deadly pathogens to new locations is giving sleepless nights to researchers engaged in providing healthcare solutions. Keeping the emerging drug resistance in mind, it is of key importance to focus our research on exploring new drugs, looking beyond the obvious solutions for immediate gains. We are witnessing a staggering rise in number of cases of infectious diseases despite various initiatives and remedial measures adopted to combat these diseases. This clearly indicates some lacunae in our current strategies for battling these diseases. Time has come to change our strategies if we want to win this battle of life and death. We need to shun our dependence on the failing drugs and search for new methods, drugs and drug targets. This can be achieved by exploring metabolic pathways of these parasites and infectious agents that can yield answers to our problems by revealing some kinks in their armor. Recent applications of high throughput screening techniques and assays in drug discovery process coupled with advances in computational biology has expedited the process of target identification and small molecule screening, pharmacophore design, peptide inhibitor design and screening and succeeded to some extent in abridging the innovation gap. Such advanced methods can be applied for supplementing our arsenals with more potent drugs against these perpetrators of misery. The war on these diseases is not new to human race and in past, we have benefitted from some rude yet efficient methods based on traditional and time-tested knowledge arising from folklore. It has now become imperative to explore this hidden wealth further to attain solutions for these maladies. Drug repositioning seems to be one effective way of grabbing some low hanging fruits for drug development. The situation warrants that the knowledge emerging from various sectors like biology, medicinal chemistry, and computational science should be integrated for designing new anti-infective agents and this can be done only by enabling strong public-private partnership in research. The quest for better drugs can be trenched by looking beyond the obvious methods and our willingness to adopt newer and safer methods and drugs while efficiently using the ones in hand.
It is with great pleasure that we introduce the special issue “Looking beyond the obvious: Search for novel targets and drugs for reducing the burden of infectious diseases”
The issue encompasses a spectrum of topics and consists of 5 excellent reviews each highlighting a specific topic. We anticipate that the scientific community will find these articles informative and beneficial.
We would like to extend our appreciation to all authors, experts in their fields, who have kindly contributed to this issue. We sincerely attribute the success of this issue to their hard work and efforts.
We express our gratitude to experts who took time off their busy schedule for reviewing the manuscripts and providing their honest opinions and invaluable insights.
We would like to thank Editor of Mini reviews in Medicinal Chemistry for giving us this excellent opportunity of preparing the hot topic issue. We take this opportunity to thank Late Dr. Patrice Talaga and appreciate his confidence in our ability to bring forth this special issue that deals with such important topic. We would like to acknowledge the tremendous help and support from Ms. Sabiha Aftab who undertook the task of publication management and correspondence and Mr. Sehrish Ashraf and Ms. Mehwish Akhter for their wonderful assistance.
We dedicate this issue to those who are devoting their time, efforts and lives for infectious diseases research in hope of giving us a better tomorrow.
Guest Editor
Dr. Neelima Arora
JawaharLal Nehru Technological University
Kukatpally
Hyderabad-500085, A.P.,
India
Email: aroraneelima123@yahoo.co.in, neelimaiict@gmail.com
Co-Guest Editor
Amit Kumar Banerjee
Bioinformatics Group, Biology Division,
Indian Institute of Chemical Technology,
Hyderabad, A.P.,
India.
amit_informatics@yahoo.com
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Targeting Tuberculosis: A glimpse of promising drug targets
Neelima Arora and Amit Kumar Banerjee
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00019]
Tuberculosis caused by Mycobacterium tuberculosis has emerged as the biggest curse of our time causing significant morbidity and mortality. Increasing resistance in mycobacterium to existing drugs calls for exploration of metabolic pathways for finding novel drug targets and also for prioritization of known drug targets. Recent advances in molecular biology, bioinformatics and structural biology coupled with availability of M. tuberculosis genome sequence have provided much needed boost to drug discovery process. This review provides a glimpse of attractive drug targets for development of anti-mycobacterial drug development.
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Daptomycin: A Review of Properties, Clinical Use, Drug Delivery and Resistance
Cláudia Vilhena and Ana Bettencourt
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00020]
Daptomycin is a branched cyclic anionic lipopeptide antibiotic that was discovered in the early 1980’s but got the FDA approval only in 2003. This novel pharmaceutical molecule has demonstrated great in vitro activity against a wide range of aerobic and anaerobic gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Daptomycin has a unique mechanism of action, not completely understood, involving a calcium-dependent dissipation of membrane potential leading to the release of intracellular ions from the cell and bacteria death. This antibiotic has been already approved for the treatment of patients with complicated skin and skin structure infections, right-sided endocarditis and bacteraemia. Local delivery of daptomycin is an emerging area of study. Current in vitro studies show that daptomycin can be eluted from polymethylmethacrylate, calcium sulfate and chitosan films. Emerging cases of resistance to daptomycin have been reported, commonly occurring by spontaneous mutations, and have been associated with prolonged use, osteomyelitis, acute myeloid leukemia and leucocyte adhesion deficiency syndrome. This review examines the most recent literature evidences on daptomycin molecular structure, mechanism of action, bacterial spectrum, clinical uses, local delivery, toxicity and resistance.
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Ru(Il)-Based Antimicrobials: Looking Beyond Organic Drugs
Ana I. Ramos, Teresa M. Braga and Susana S. Braga
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00021]
This review deals with the bactericidal, anti-fungal and even anti-parasitary properties of ruthenium complexes, both inorganic and organometallic, establishing comparisons between these and the available commercial drugs.
The description is mostly composed of results found in the literature of the past two decades, complemented with relevant results from our group’s research on antimicrobial ruthenium complexes.
The complexes are divided into five groups according to the kind of ligands, geometry and chemical nature.
The first group comprises of ruthenium octahedral complexes with Schiff bases, the most well explored kind of ruthenium antimicrobials. The second group comprises of complexes with planar ligands and an overall more flattened geometry, designed for DNA intercalation. In the following two groups, ruthenium complexes feature a particular functionality, which is, in one case, the presence of the PTA ligand for higher solubility in water, and, in the second, the mimicry of an active organic drug. Finally, a small section presents the most recent results on supramolecular antimicrobials comprising ruthenium, in particular a polymer and a cyclodextrin adduct.
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Targeting Strategies for Human Immunodeficiency Virus: A Combinatorial Approach
Shailendra K. Saxena, Ankur Gupta, Kamble Bhagyashree, Rakhi Saxena, Neelima Arora, Amit K. Banerjee,Anil K. Tripathi, Nimisha Gandhi and Madhavan P.N. Nair
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00022]
The battle between human and the Human immunodeficiency virus (HIV) is on, with both of them rapidly improving their attacking and defense strategies. Many therapeutic agents for HIV infection have been designed and developed, However there are various aspects, like novel targets against HIV, which are yet to be unfolded with a goal of designing and developing novel drug molecules against HIV. This article reviews the current status and innovative new options for antiretroviral therapy for HIV and also discusses the various mechanisms of action for each class of drugs, and the problems yet to be solved with respect to HIV as a target for improvised treatment against AIDS.
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Carbohydrate mimics and lectins: a source of new drugs and therapeutic opportunities
José J. Reina and Anna Bernardi
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00023]
Mimics of oligosaccharides capable of interfering with lectin activity are currently being pursued by a number of groups in an effort to produce tools for glycobiology and to design antagonists of medically relevant lectins. The field is reviewed in this chapter. After a brief overview of the state of the art, examples from our and others’ studies on the dendritic cell receptor DC-SIGN are illustrated.
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The Medicinal Chemistry Of (—)-Shikimic Acid
Amalia M. Estévez, Ramón J. Estévez and Juan C. Estévez
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00024]
Shikimic acid, a natural compound is a key intermediate in the biosynthesis of amino acids. Consequently, this derivative is widely present in many plants and has interesting biological properties. But besides the pharmacological relevance of shikimic acid itself, it is also an intermediate in the synthesis of many drugs, being the most relevant the antiviral agent oseltamivir (tamiflu). Here we present a short overview on recent natural, biotechnological and synthetical sources of shikimic acid, togheter with pharmacological applications of this compound and a selections of derivatives, including Oseltamivir (Tamiflu™).
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Recent Progress on Fucosyltransferase Inhibitors
Pedro Merino, Tomás Tejero, Ignacio Delso, Ramon Hurtado-Guerrero, Asier Gómez‑SanJuan and David Sádaba
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00025]
Fucosyltransferases (FucTs) are enzymes that transfer L-fucose from GDP-fucose to a glycoside or a peptide. They have important roles in a variety of diseases including cancer and autoimmune disorders, viral and bacterial infections and inflammatory processes, and thus they represent important drug targets for the development of agents for the treatment of such disorders. This review highlights recent developments regarding carbohydrate mimics as inhibitors of FucTs. The most recent and relevant synthetic strategies are described.
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Mycalamides, Pederin and Psymberin as Natural Carbohydrates and Potential Antitumor Agents: Past and Future Perspectives
Zbigniew J. Witczak, Ricky M. Rampulla Jr. and Ajay Bommareddy
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00026]
The mycalamide class of potent antiviral and antitumor natural compounds originally isolated from marine sponges in 1988 is a new interdisciplinary approach to molecular recognition. We review new synthetic approaches to this new family of natural products with remarkable biological activity. Some biological evaluation data are compiled and compared to other structurally similar molecular targets.
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Carbohydrate based Potential Chemotherapeutic Agents: Recent Developments and their Scope in Future Drug Discovery
Vinod K. Tiwari, Ram C. Mishra, Anindra Sharma and Rama P. Tripathi
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00027]
In addition to being valuable source of energy, carbohydrates, one of the main dietary components, are integral parts of the cell. As extra- & intracellular molecules they act as cell surface receptor and also as signaling molecules playing predominant role in molecular recognition and many other cellular processes. The clear understanding of their role in the various important biological events has led to the demand for easy access of diverse glycoconjugates for their complete chemical and biological investigations. Several carbohydrate-based molecules both of synthetic and natural origin are known for their wide range of pharmacological activities and even many of them are clinically used to treat different ailments. Due to their structural diversity in terms of functional groups, ring size and linkages they are valuable scaffolds in drug discovery processes. Because of the hydrophilic nature of monosaccharides they offer good water solubility, optimum pharmacokinetics and decreased toxicity. These naturally occurring molecules have therefore been extensively used to access diverse library of compounds with great chemotherapeutic importance. This review highlights an overview of development of carbohydrate-based molecules from others and our lab which have shown promising biological activity against front line diseases.
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Diels-Alder Cycloaddition in the Synthesis of 1-Azafagomine, Analogues, and Derivatives as Glycosidase Inhibitors
Daniela A. L. Salgueiro, Cristina E. A. Sousa, A. Gil Fortes and M. José Alves
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00028]
This comprehensive review deals with the synthesis of 1-azafagomine, analogues, and derivatives having the Diels-Alder cycloaddition as the key step. Most of the compounds referred are racemic or have been resolved by lipase transesterification. There are two asymmetric cycloadditions leading to 1-azafagomine or to an analogue. In one case both enantiomers of 1-azafagomine were prepared together with a pair of derivatives. The study comprises glycosidase inhibition studies of the target compounds to a set of glycosidic enzymes, and evidenced molecular features that enhance or diminish their activity as glycosidase inhibitors.
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Advances in the Synthesis of Calystegines and Related Products and their Biochemical Properties
M.S. Pino-Gonzalez, N. Oña and A. Romero-Carrasco
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00029]
The revision of thestructures and properties of Calystegines shows that they can be regarded as carbohydrate mimics, with related biological activities and peculiar characteristics. Not only they can be isolated from food plants, but they can be obtained from a variety of monosaccharide derivatives and of non-carbohydrate products. Althoug several synthetic calystegine analogues have been reported as glycosidase inhibitors, new, more potent and effective inhibitors are required.
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Spirocyclic Nucleosides In Medicinal Chemistry: An Overview
Raquel G. Soengas and Sandrina Silva
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00030]
This review describes some spiro- and pseudospironucleoside derivatives as well as their biological and pharmacological applications.
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Development of Aminoglycoside Antibiotics by Carbohydrate Chemistry
Lina Guo, Yue Wan, Xin Wang, Peng George Wang and Wei Zhao
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00031]
With the development of glycomics, more and more carbohydrate mimetics were used to investigate the interactions between carbohydrate-proteins, especially in physiological and pathological processes, molecular recognition, signal transduction, cell communication, cell differentiation and developmental events. Recently, because of the drug-resistance of microorganisms and the development of antibiotics, the interactions between carbohydrate mimetics and RNAs are becoming hot issue.
Aminoglycosides, one family of important antibiotics, can bind with 30S subunits of rRNA to prevent the normal translations of proteins, inhibit the proteins involving in the drug-resistance. In this review, the latest advances in development and applications of aminoglycosides are summarized and the detailed descriptions on the SAR study (Structure-activity relationship) of aminoglycoside derivatives are discussed.
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Fullerene Derivative as anti-HIV Protease Inhibitor: Molecular Modeling and QSAR Approaches
Medhat Ibrahim, Noha A. Saleh, Wael M. Elshemey and Anwar A. Elsayed
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00032]
A Fullerene based system is modified in order to increase its solubility and enhance its ability to carry a protein-like structure. The modified structure, which is proposed to act as HIV-1 protease inhibitor, is [C60–C2H4N–(2,4-XCOCH2OH)C6H4], where the X atom is either O, S or Se. The geometry optimization, vibrational spectra and thermodynamics were performed using semiempirical quantum mechanical PM3 method in order to study the proposed compounds. Furthermore, the quantitative structure activity relationship (QSAR) properties of the compounds are calculated at the same level of theory. Results indicate a possible use of the investigated structures as HIV-1 protease inhibitors. The compound containing oxygen being more stable compared to the other two compounds.
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Review of Theoretical Studies for Prediction neurodegenerative inhibitors
Francisco Prado-Prado and Isela García
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00033]
Alzheimer's disease (AD) is characterize with several pathologies, this disease is a neuropathological lesion in brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. AD is the most prevalent form of dementia, and current indications show that twenty-nine million people live with AD worldwide, a figure expected rise exponentially over the coming decades. Clearly, blocking disease progression or, in the best-case scenario, preventing AD altogether would be of benefit in both social and economic terms. However, current AD therapies are merely palliative and only temporarily slow cognitive decline, and treatments that address the underlying pathologic mechanisms of AD are completely lacking. While familial AD (FAD) is caused by autosomal dominant mutations in either amyloid precursor protein (APP) or the presenilin (PS1, PS2) genes. First, we revised 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking of β and γ-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and docking for GSK-3α and GSK-3β with different compound to find out the structural requirements.
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Evaluation of the Pharmacological Descriptors Related to the Induction of Antidepressant Activity and its Prediction by QSAR/QRAR Methods
Speranta Avram, Catalin Buiu, Daniel Duda-Seiman and Corina Duda-Seiman
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00034]
Antidepressants are psychiatric agents used for the treatment of different types of depression being at present amongst the most commonly prescribed drugs, while their effectiveness and adverse effects is still the subject of many studies. To reduce the inefficiency of known antidepressants caused by their side-effects, many research efforts have recently focused on the development of improved strategies for new antidepressants drug design. For this reason it is necessary to apply very fast and precise techniques, such as QSAR (Quantitative Structure-Activity Relationships) and QRAR (Quantitative Retention-Activity Relationship), which are capable to analyze and predict the biological activity for these structures, taking in account the possible changes of the molecular structures and chromatographic parameters. We discuss the pharmaceutical descriptors (van der Waals, electrostatic, hydrophobicity, hydrogen donor/acceptor bond, Verloop's parameters, polar area) involved in QSAR and also chromatographic parameters involved in QRAR studies of antidepressants. Antidepressant activities of alkanol piperazine, acetamides, arylpiperazines, thienopyrimidinone derivatives (as preclinical antidepressants) and also the antidepressants already used in clinical practice are mentioned.
Pharmacological Descriptors Related to the Induction of Antidepressant Activity
Speranta AVRAM
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00035]
Antidepressants are psychiatric agents used for the treatment of different types of depression being at present amongst the most commonly prescribed drugs, while their effectiveness and adverse effects is still the subject of many studies. To reduce the inefficiency of known antidepressants caused by their side-effects, many research efforts have recently focused on the development of improved strategies for new antidepressants drug design. For this reason it is necessary to apply very fast and precise techniques, such as QSAR (Quantitative Structure-Activity Relationships) and QRAR (Quantitative Retention-Activity Relationship), which are capable to analyze and predict the biological activity for these structures, taking in account the possible changes of the molecular structures and chromatographic parameters. We discuss the pharmaceutical descriptors (van der Waals, electrostatic, hydrophobicity, hydrogen donor/acceptor bond, Verloop's parameters, polar area) involved in QSAR and also chromatographic parameters involved in QRAR studies of antidepressants. Antidepressant activities of alkanol piperazine, acetamides, arylpiperazines, thienopyrimidinone derivatives (as preclinical antidepressants) and also the antidepressants already used in clinical practice are mentioned.
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Relationship between phenol-induced cytotoxicity and experimental inhibition rate constant or a theoretical parameter
Seiichiro Fujisawa and Yoshinori Kadoma
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00036]
We synthesized various dimer forms of 2-methoxyphenols and 2-tert-butylphenols, as dimers such as curcumin exhibit potent antioxidant and anti-inflammatory activity. We investigated the QSARs between the cytotoxicity and independent variables; kinetic parameters (inhibition rate constant (kinh/kp), stoichiometric factor (n)) or DFT-based theoretical parameters (i.e. phenolic O-H bond dissociation enthalpy (BDE), ionization potential according to Koopman’s theorem (IP), LUMO, absolute hardness (η), electronegativity (χ) and electrophilicity (ω)) for 2-methoxyphenols and 2-tert- or 2,6-di-tert-butylphenols. The cytotoxicity of these phenols against human tumor cells (HSG, HL60) and/or human gingival fibroblasts (HGF) showed a marked negative linear relationship to kinh/kp, suggesting that the cytotoxicity of phenols may be related to radical reactions. By contrast, a linear relationship between the cytotoxicity and η-term was demonstrated; 2-methoxyphenols showed a negative slope, whereas 2-tert- or 2,6-di-tert-butylphenols showed a positive slope. Also, the cytotoxicity of tert-butylphenols was linearly dependent on the LUMO-term, showing a positive slope. The cytotoxicity of methoxy-substituted monophenols toward both HSG and HGF cells was related to both log P and η-terms. Also, that of X-phenols toward murine L-1210 cells was related to both log P and η or IP-terms, determined from a dataset reported by Zhang et al., 1998. It was concluded that the phenol-induced cytotoxicity was attributable to radical reactions resulting from the terms (kinh/kp, IP, η, and LUMO) in QSAR. The LUMO-dependent cytotoxicity of 2-tert- or 2,6-di-tert-butylphenols may be related to their quinone oxidation products. Experimental and theoretical parameters provide a useful approach for analysis of the cytotoxicity for phenolic compounds.
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On the use of the metric rm2 as an effective tool for validation of QSAR models in computational drug design and predictive toxicology
Kunal Roy and Indrani Mitra
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00036]
Validation of quantitative structure-activity relationship (QSAR) models plays a key role for the selection of robust and predictive models that may be employed for further activity prediction of new molecules. Traditionally, QSAR models are validated based on classical metrics for internal (Q2) and external validation (R2pred). Recently, it has been shown that for data sets with wide range of the response variable, these traditional metrics tend to achieve high values without truly reflecting absolute differences between the observed and predicted response values, as in both cases the reference for comparison of the predicted residuals is the deviations of the observed values from the training set mean. Roy et al. have recently developed a new parameter, modified r2 (rm2), which considers the actual difference between the observed and predicted response data without consideration of training set mean thereby serving as a more stringent measure for assessment of model predictivity compared to the traditional validation parameters (Q2 and R2pred). The rm2 parameter has three different variants: (i) rm2(LOO) for internal validation, (ii) rm2(test) for external validation and (iii) rm2(overall) for analyzing the overall performance of the developed model considering predictions for both internal and external validation sets. Thus, the rm2 metrics strictly judge the ability of a QSAR model to predict the activity/toxicity of untested molecules. The present review provides a survey of the development of different rm2 metrics followed by their applications in modeling studies for selection of the best QSAR models in different reports made by several workers.
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Quantitative Structure-Activity Relationship (QSAR) Analysis to Predict Drug-Drug Interactions of ABC transporter ABCG2
Toshihisa Ishikawa, Hiroyuki Hirano, Hiakru Saito, Kazumi Sano and Yoji Ikegami
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00037]
Quantitative structure-activity relationship (QSAR) analysis is a practical approach by which chemical structure is quantitatively correlated with biological activity or chemical reactivity. Human ABC transporter ABCG2 exhibits broad substrate specificity toward structurally diverse compounds. To gain insight into the relationship between the molecular structures of compounds and the interaction with ABCG2, we have developed an algorithm that analyzes QSAR to evaluate ABCG2-drug interactions. In addition, to support QSAR analysis, we developed a high-speed screening method for analyzing the drug-drug interactions of ABCG2. Based on both experimental results and computational QSAR analysis data, we propose a hypothetical mechanism underlying ABC-mediated drug transport and its interaction with drugs.
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Binding modes and pharmacophore modelling of thermolysin inhibitors
Mahmud Tareq Hassan Khan, Yimingjiang Wuxiuer and Ingebrigt Sylte
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00038]
In the present paper 25 known thermolysin inhibitors were docked into thermolysin using the Internal Coordinate Mechanics (ICM™) software. Pharmacophore models based on thermolysin binding modes and activity profiles were generated using the LigandScout™ program. The docking studies indicated that all 25 inhibitors coordinated the catalytic zinc in bidentate or monodentate geometry. A ‘three-point’ pharmacophore model was proposed which consisted of a hydrophobic group, a negative ionizable group and a hydrogen bond acceptor group. Finally the pharmacophore model has been tested against a small compound library containing 18 highly, moderately, less active as well as inactive compounds. The screening indicated that the pharmacophore model could, identify highly active compounds in front of inactive or less active ones.
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QSAR in Oral Bioavailability: Specificity or Integrality?
Miguel Ángel Cabrera-Pérez, Hai Pham-The, Marival Bermejo, Isabel González Álvarez, Marta González Álvarez and Teresa M Garrigues
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00039]
During the last decade the technological advances in the drug discovery field have changed the absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles of New Chemical Entities (NCEs). Among the ADMET processes, the absorption plays an important role in the research and development of more effective oral drugs. Although significant progress have been made in the in vitro, in situ and in vivo experimental determinations of the absorption process, the development of in silico methodologies has emerged as a less cost and fast alternative to predict ADMET properties. Even several in silico models have been described in the literature to predict oral bioavailability and related properties, the prediction accuracy and their potential use is still limited. The uncertain and highly variable experimental data, the lack of a complete experimental and theoretical validation of in silico approach, and above all, the multi-factorial nature involved in the oral absorption term, become the development of in silico models to predict these dispositional profiles in a thorny task. The present review discusses several important progresses regarding the QSAR approaches used in the development of predictive oral bioavailability models. As a remarkable conclusion of our analysis, we highlighted the importance of fixing the problem associated with data resource, as well as improving the reliability of in silico results. Optimization of individual properties along the absorption process must be integrated in a multi-objective scene for studying oral bioavailability behavior in the early drug discovery and development.
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Estimation of the Binding Free Energy by Linear Interaction Energy Models
Orazio Nicolotti, Marino Covertino, Francesco Leonetti, Marco Catto, Saverio Cellamare and Angelo Carotti
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00040]
Since Hansch's extra thermodynamic multi-parameter approach, originally coined as Linear Free Energy Relationship, great efforts in medicinal chemistry have been made to properly estimate the binding free energy. Despite the often small amount, its value is however very critical in determining a successful binding. As a result, its correct estimate may provide a guide for a prospective rational drug design. The calculation of the absolute binding free energies is however a very challenging task as it requires a rigorous treatment of a number of physical terms that are both very time demanding and to some extent not immediately interpretable. In view of this, the introduction of some numerical approximations has permitted to develop the so called Linear Interaction Energy method that, at present, constitutes the best compromise among accuracy, speed of computation and easy interpretation. The initially developed Linear Interaction Energy method was subsequently revisited and several important improvements have been made. Significant examples are the Extended Linear Response, the surface generalized Born LIE, the molecular mechanics generalized Born surface area, the linear interaction energy in continuum electrostatics as well as its quantum mechanics variant. Principles and selected applications of these methods will be herein reviewed.
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A Critical View on Antimalarial Endoperoxide QSAR Studies
Róbson Ricardo Teixeira, José Walkimar de Mesquita Carneiro, Martha T. de Araújo and Alex G. Taranto
[FULL-TEXT INQUIRY] [BSP/MRMC/E-Pub/00041]
Malaria is one of the most dangerous diseases in developing countries. The chemotherapy of malaria has been based on drugs developed more than half a century ago. These drugs are continuously losing their efficacy, mainly due to multi-drug resistance developed by the malaria-causing parasite. In the last three decades, artemisinin and artemisinin-like compounds have proven to be efficient alternatives to the chemotherapeutic control of malaria. These facts have led to an increasing interest in the development of Quantitative Structure Activity Relantioship (QSAR) models for these compounds. This work presents a critical view on some QSAR models, and shows that, due to lack of a rigorous selection of the descriptors entering the models, most of them are unable to accurately indicate the molecular cause of biological activity. Some reasons for the weakness of the published models are discussed.
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